Abstract: Protein-protein interactions (PPIs) are central factors in all cellular signaling and gene regulation protein networks, and their misregulation has been associated with a variety of diseases, notably cancer. Inevitably, many PPIs are biologically compelling targets for drug discovery. However, PPIs feature large, flat binding surfaces, lacking the tight-binding cavities that define typical drug targets. Accordingly, many PPIs pose a fundamental thermodynamic challenge to the development of conventional small molecule modulators. A promising PPI inhibitor discovery strategy is to use miniature protein domain mimetics (PDMs) to reproduce the key interface contacts utilized by nature. PDMs are advantageous as medium-sized molecules with high surface complementarity and a broader set of contact points than typical small molecules, but are still limited because?by definition?only a portion of the total PPI binding energy is captured in the interaction. The binding affinity of the synthetic domains is often lower than the cognate full-length proteins. Targeted covalent inhibition is an orthogonal therapeutic approach traditionally employed to enhance binding affinities of small molecules, but the approach has a potential drawback as the high reactivity of typical covalent warheads may lead to nonspecific interactions and toxicity. Here we propose to develop computational methods for a new design strategy that will leverage the strengths of these two methods?PDMs and covalent inhibition? while simultaneously mitigating their respective limitations. The focus of the effort is to rationally discover potent inhibitors that will non-covalently recognize and then covalently target protein- protein binding interfaces with exquisite specificity.